Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid

Vitamin A (retinol) is a nutrient that is essential for developmental regulation but toxic in large amounts. Previous genetic studies have revealed that alcohol dehydrogenase Adh1 is required for efficient clearance of excess retinol to prevent toxicity, thus demonstrating that the mechanism involves oxidation of excess retinol to retinoic acid (RA). Whereas Adh1 plays a dominant role in the first step of the clearance pathway (oxidation of retinol to retinaldehyde), it is unknown what controls the second step (oxidation of retinaldehyde to RA). We now present genetic evidence that aldehyde dehydrogenase Aldh1a1, also known as retinaldehyde dehydrogenase Raldh1, plays a dominant role in the second step of retinol clearance in adult mice. Serum RA levels following a 50 mg/kg dose of retinol were reduced 72% in Raldh1 -/- mice and 82% in Adh1 -/- mice. This represented reductions in RA synthesis of 77–78% for each mutant after corrections for altered RA degradation in each. After retinol dosing, serum retinaldehyde was increased 2.5-fold in Raldh1 -/- mice (indicating defective retinaldehyde clearance) and decreased 3-fold in Adh1 -/- mice (indicating defective retinaldehyde synthesis). Serum retinol clearance following retinol administration was decreased 7% in Raldh1 -/- mice and 69% in Adh1 -/- mice. LD50 studies indicated a small increase in retinol toxicity in Raldh1 -/- mice and a large increase in Adh1 -/- mice. These observations demonstrate that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulating retinol rather than retinaldehyde. Vitamin A (retinol) is a nutrient that is essential for developmental regulation but toxic in large amounts. Previous genetic studies have revealed that alcohol dehydrogenase Adh1 is required for efficient clearance of excess retinol to prevent toxicity, thus demonstrating that the mechanism involves oxidation of excess retinol to retinoic acid (RA). Whereas Adh1 plays a dominant role in the first step of the clearance pathway (oxidation of retinol to retinaldehyde), it is unknown what controls the second step (oxidation of retinaldehyde to RA). We now present genetic evidence that aldehyde dehydrogenase Aldh1a1, also known as retinaldehyde dehydrogenase Raldh1, plays a dominant role in the second step of retinol clearance in adult mice. Serum RA levels following a 50 mg/kg dose of retinol were reduced 72% in Raldh1 -/- mice and 82% in Adh1 -/- mice. This represented reductions in RA synthesis of 77–78% for each mutant after corrections for altered RA degradation in each. After retinol dosing, serum retinaldehyde was increased 2.5-fold in Raldh1 -/- mice (indicating defective retinaldehyde clearance) and decreased 3-fold in Adh1 -/- mice (indicating defective retinaldehyde synthesis). Serum retinol clearance following retinol administration was decreased 7% in Raldh1 -/- mice and 69% in Adh1 -/- mice. LD50 studies indicated a small increase in retinol toxicity in Raldh1 -/- mice and a large increase in Adh1 -/- mice. These observations demonstrate that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulating retinol rather than retinaldehyde. Retinoic acid (RA) 1The abbreviations used are: RA, retinoic acid; ADH, alcohol dehydrogenase; Adh1, mouse class I ADH gene; ALDH, aldehyde dehydrogenase; Aldh1a1, official gene name for mouse Raldh1; AUC, area under curve; CYP, cytochrome P450; RALDH, retinaldehyde dehydrogenase; Raldh1, mouse RALDH1 gene; HPLC, high pressure liquid chromatography. is a metabolic derivative of vitamin A (retinol) that regulates developmental pathways in chordate animals (1Clagett-Dame M. DeLuca H.F. Annu. Rev. Nutr. 2002; 22: 347-381Crossref PubMed Scopus (384) Google Scholar). RA functions in the control of gene expression by serving as a ligand for several nuclear RA receptors and retinoid X receptors (2Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2604) Google Scholar). Whereas in vitro studies suggested that all-trans-RA (a ligand for RA receptors) and its isomer 9-cis-RA (a ligand for retinoid X receptors) might both regulate gene expression (3Heyman R.A. Mangelsdorf D.J. Dyck J.A. Stein R.B. Eichele G. Evans R.M. Thaller C. Cell. 1992; 68: 397-406Abstract Full Text PDF PubMed Scopus (1567) Google Scholar), in vivo studies indicate that only all-trans-RA is needed physiologically to correct a lethal genetic defect in RA synthesis (4Mic F.A. Molotkov A. Benbrook D.M. Duester G. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 7135-7140Crossref PubMed Scopus (183) Google Scholar). Retinoid metabolic enzymes ensure that sufficient all-trans-RA is produced from retinol to control RA signaling in target tissues (5Duester G. Eur. J. Biochem. 2000; 267: 4315-4324Crossref PubMed Scopus (495) Google Scholar). Also, mechanisms exist to prevent excessive accumulation of RA and retinol as high levels of either of them are teratogenic during development or toxic to adult animals (6Kochhar D.M. Acta Pathol. Microbiol. Scand. Suppl. 1967; 70: 398-404Crossref Scopus (188) Google Scholar, 7Kamm J.J. J. Am. Acad. 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Biochemistry. 2003; 42: 776-784Crossref PubMed Scopus (37) Google Scholar) that oxidize retinol to retinaldehyde as well as cytosolic aldehyde dehydrogenases (ALDH), also known as retinaldehyde dehydrogenases (RALDH), that oxidize retinaldehyde to RA (18Lee M.-O. Manthey C.L. Sladek N.E. Biochem. Pharmacol. 1991; 42: 1279-1285Crossref PubMed Scopus (125) Google Scholar, 19McCaffery P. Posch K.C. Napoli J.L. Gudas L. Dräger U.C. Dev. Biol. 1993; 158: 390-399Crossref PubMed Scopus (132) Google Scholar, 20Labrecque J. Dumas F. Lacroix A. Bhat P.V. Biochem. J. 1995; 305: 681-684Crossref PubMed Scopus (89) Google Scholar, 21Grün F. Hirose Y. Kawauchi S. Ogura T. Umesono K. J. Biol. Chem. 2000; 275: 41210-41218Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 22Gagnon I. Duester G. Bhat P.V. Biochim. Biophys. Acta. 2002; 1596: 156-162Crossref PubMed Scopus (53) Google Scholar). Various cytochrome P450 (CYP) enzymes deactivate RA by oxidation to more polar metabolites such as 4-oxo-RA that are more easily excreted (23Roberts E.S. Vaz A.D.N. Coon M.J. Mol. Pharmacol. 1992; 41: 427-433PubMed Google Scholar, 24White J.A. Guo Y.D. Baetz K. Beckett-Jones B. Bonasoro J. Hsu K.E. Dilworth F.J. Jones G. Petkovich M. J. Biol. Chem. 1996; 271: 29922-29927Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 25McSorley L.C. Daly A.K. Biochem. Pharmacol. 2000; 60: 517-526Crossref PubMed Scopus (130) Google Scholar). The combined activity of RA-synthesizing and RA-degrading enzymes determines the steady-state level of RA in target tissues for signaling plus ensures that excess retinol or RA is metabolized to excretable forms. Within the enzyme families listed above, genetic studies are beginning to reveal the identity of individual members that function in retinoid metabolism in vivo. Adh1 -/- mice do not exhibit defects in growth or survival but display greatly reduced metabolism of a dose of retinol to RA and increased retinol toxicity (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). high activity for oxidation of retinol to is for clearance of retinol to prevent its toxic -/- mice display a small in metabolism of a dose of retinol to RA, but more defects in growth and survival A. X. Deltour L. Foglio M.H. Martras S. Farrés J. Parés X. Duester G. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). activity for oxidation of retinol to but is for synthesis of RA needed for RA signaling during studies have that high levels in is the enzyme for the clearance of excess retinol to prevent toxicity, plays a role in A. X. Duester G. Eur. J. Biochem. 2002; PubMed Scopus Google Scholar). -/- mice do not display a in metabolism of a dose of retinol to RA but are more to defects in growth and survival during vitamin A (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). high activity for oxidation of retinol to is needed to produce sufficient RA for developmental RA signaling when retinol levels are of -/- mice that the short-chain enzyme in oxidation of to for of the but is evidence that plays an in vivo role in RA synthesis K. K. K. Mol. Biol. 2000; PubMed Scopus Google Scholar, E.Y. Lai K. J. Blaner W.S. M.D. P. Wolgemuth D.J. J. Res. 2002; Full Text Full Text PDF PubMed Google Scholar). -/- mice have developmental defects and greatly reduced RA, that plays an in vivo role in oxidation of retinaldehyde to RA to activate RA signaling during development K. P. P. PubMed Scopus Google Scholar, F.A. Cuenca A.E. Duester G. 2002; Google Scholar). -/- mice display high RA levels and defects to during RA that the of to oxidize RA to polar metabolites 4-oxo-RA excessive accumulation of RA during development Y. C. J. Y. J. Dev. PubMed Scopus Google Scholar, S. P. B. P. Petkovich M. Dev. PubMed Scopus Google Scholar). genetic studies have that the oxidative of RA produced by are not needed for RA signaling during development but are degradation K. S. B. Petkovich M. P. P. 2002; PubMed Scopus Google Scholar). These genetic studies indicate that enzymes and of correct RA levels for developmental RA or clearance of excess retinol to prevent toxicity in adult the first the RA produced is used to regulate developmental but in the second the RA produced is an in the degradation to prevent retinol to synthesis and degradation of RA for developmental for and have thus of the oxidation for of retinol toxicity in adult a role for in the first step but enzymes physiologically in the have not RALDH1 was the first of the to in vitro activity for oxidation of retinaldehyde to RA (18Lee M.-O. Manthey C.L. Sladek N.E. Biochem. Pharmacol. 1991; 42: 1279-1285Crossref PubMed Scopus (125) Google Scholar, 20Labrecque J. Dumas F. Lacroix A. Bhat P.V. Biochem. J. 1995; 305: 681-684Crossref PubMed Scopus (89) Google Scholar). of mouse RALDH1 to RA synthesis in vivo Duester G. Eur. J. Biochem. PubMed Scopus Google Scholar). RALDH1 is in the and adult as well as in adult in mouse P. P. G. Dräger U.C. 1991; Google Scholar), R. Exp. Res. 1992; PubMed Scopus Google Scholar, R. E.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and Duester G. Dev. PubMed Scopus Google Scholar). have that Raldh1 -/- mice do not exhibit developmental defects in the or tissues X. Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Blaner W.S. Duester G. Mol. Biol. 2003; PubMed Scopus Google Scholar). RALDH1 is than in tissues but more than in adult mouse tissues I. Duester G. Dev. PubMed Google Scholar), that RALDH1 a role in adult retinoid metabolism to have retinoid metabolism in Raldh1 -/- mice following a dose of retinol and with studies Adh1 -/- mice A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) as well as studies Adh1 -/- mice. indicate that RALDH1 plays a role in oxidation of retinaldehyde to RA for clearance of excess retinol in adult thus downstream of -/- mice were as a gene that from the Raldh1 gene X. Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Blaner W.S. Duester G. Mol. Biol. 2003; PubMed Scopus Google Scholar). The and Adh1 -/- mice used have A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, L. Foglio M.H. Duester G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the mice were for and of Serum Retinoic and were as M.D. Eckhoff C. I. G. Arch. 1992; PubMed Scopus Google Scholar). or all-trans-RA were in and were by a dose of 50 mg/kg for retinol or mg/kg for several following retinoid was and were from of serum under and and all-trans-RA were by a as A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of Serum was in and by a dose of was after and as of the and were in a to from to was after to the more as J. K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). Serum was with of and of After a the was with of were and under The was in of and of was the was a an a of and of of and of was a and A of and was by of with as This was used to the and the and were used to and of was Retinol 50 were of retinol to the lethal dose as (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of the of the mice mice were was in and by from to of the dose was was for after retinol The of and F. J. Pharmacol. Exp. Google Scholar) were used to the in the of 50 or of the mice by plus the for the LD50 of RA synthesis or degradation was by the area under the was for the of Raldh1 -/- that Raldh1 -/- mice were the and to be and defects in growth or survival X. Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Blaner W.S. Duester G. Mol. Biol. 2003; PubMed Scopus Google Scholar). a mouse RALDH1 I. Duester G. Dev. 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Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Raldh1 -/- mice a RA of A of for mice and the mutant that Raldh1 in a 72% in serum RA during the following retinol Adh1 in an 82% in serum RA These that RALDH1 and are both needed to excess retinol to under for the of Raldh1 or Adh1 synthesis or degradation of all-trans-RA and clearance of acid or synthesis were from in degradation were from in or clearance were from in or were from in were from in were from in in a RA in Raldh1 -/- and Adh1 -/- the in serum RA in Raldh1 -/- mice after retinol administration is to a in RA synthesis or altered RA degradation in a RA is metabolized to polar degradation Sporn M.B. Roberts A.B. Goodman D.S. The Press, Google Scholar), to a in mouse serum of R.B. Ashenfelter K.O. Eckhoff C. Levin A.A. Shapiro S.S. Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. 2nd Ed. Raven Press, Ltd., New York1994: 545-572Google Scholar). of mice with mg/kg RA, serum RA was to the of clearance studies have that with dose of RA in serum RA of for mice and for Adh1 -/- mice A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Raldh1 -/- mice a RA of A of for mice and the that Raldh1 in a increase in serum RA during the following RA Adh1 in a in serum RA is a small in RA degradation in Raldh1 -/- mice and a small increase in RA degradation in Adh1 -/- mice. The RA degradation are small for both the that the reductions in RA following retinol administration are primarily the of in RA of Retinol in Raldh1 -/- and Adh1 -/- of retinol in mouse serum is (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). have that serum retinol levels after retinol administration are increased to in mice and to in Adh1 -/- retinol clearance in Adh1 -/- mice A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). retinol clearance was a for Raldh1 and Adh1 -/- mice with 50 mg/kg retinol A of for mice and the mutant that Raldh1 in a 7% increase in serum retinol during the following retinol Adh1 in a 69% increase This that Raldh1 -/- mice have a small in retinol Adh1 -/- mice have a large in retinol of Retinol the of the by ADH retinaldehyde Arch. Biochem. PubMed Scopus Google Scholar) and as oxidation of retinaldehyde to RA by is efficient (18Lee M.-O. Manthey C.L. Sladek N.E. Biochem. Pharmacol. 1991; 42: 1279-1285Crossref PubMed Scopus (125) Google Scholar, S. J. Biol. Chem. Full Text PDF PubMed Google Scholar), retinaldehyde is present levels in tissues with the of the it functions in the G. PubMed Scopus Google Scholar). that retinaldehyde was in serum of Raldh1 and Adh1 -/- mice to retinol of was after retinol administration serum retinaldehyde was in in Raldh1 -/- and in Adh1 -/- mice during clearance of excess of Raldh1 to excessive accumulation of of Adh1 to a in retinaldehyde Retinol in Raldh1 -/- and Adh1 -/- retinol LD50 for mice and Adh1 -/- mice demonstrating that Adh1 plays a large role in retinol toxicity (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). the retinol LD50 for Raldh1 -/- mice was to be to the of when the These that Raldh1 retinol toxicity but that Adh1 plays a of or retinol lethal dose The for and Adh1 -/- mice were (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google for LD50 are in The for LD50 are in in a studies evidence that Raldh1 is needed to produce RA for developmental signaling pathways X. Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Blaner W.S. Duester G. Mol. Biol. 2003; PubMed Scopus Google Scholar). the that Raldh1 plays a role in retinol clearance in vivo. is that Raldh1 functions downstream of Adh1 in the oxidative clearance of excess retinol metabolism to the oxidation of retinol to retinaldehyde by is a (10Boleda M.D. Saubi N. Farrés J. Parés X. Arch. Biochem. Biophys. 1993; 307: 85-90Crossref PubMed Scopus (180) Google Scholar, Arch. Biochem. PubMed Scopus Google Scholar, J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar), efficient clearance of retinol that retinaldehyde be metabolized and RALDH1 by retinaldehyde to This function Raldh1 from plays a role in the of RA for developmental RA signaling K. P. P. PubMed Scopus Google Scholar, F.A. Cuenca A.E. Duester G. 2002; Google Scholar). to be Raldh1 functions in of RA synthesis needed for RA signaling in either adult or animals in to its function in retinol The genetic studies have that RALDH1 large of retinaldehyde to RA in adult mice as of the oxidative pathway to toxic levels of retinol by retinol of mg/kg were needed to the RA and retinaldehyde produced in Raldh1 -/- level of retinol not be in the of animals in the demonstrating decreased survival and increased toxicity in Adh1 -/- mice with a retinol are to for animals as as the of retinol be by in vitamin A (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). that in animals and RALDH1 are for of accumulation of We by of Adh1 -/- mice and mice with of retinol that is for of the metabolism of retinol to RA during the following retinol administration A. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). is for 82% of the RA for an increase in RA degradation in Adh1 -/- mice and after for increased RA degradation the that RALDH1 is for 72% of the RA for an in RA degradation in Raldh1 -/- mice and after for decreased RA degradation The of Adh1 or Raldh1 RA degradation are demonstrating that the reductions in serum RA following administration of retinol to Adh1 -/- and Raldh1 -/- mice are the of reduced RA the that each mutant RA synthesis by the that are the metabolic the of 3-fold reduced serum retinaldehyde levels in Adh1 -/- mice following retinol evidence that is the dominant oxidation of excess retinol to retinaldehyde. the of 2.5-fold serum retinaldehyde levels in Raldh1 -/- mice following retinol evidence that RALDH1 is the dominant oxidation of excess retinaldehyde to a of RALDH1 in accumulation of retinaldehyde produced by We have that RA produced following a dose of retinol is not the toxic in adult Adh1 -/- mice have RA increased toxicity (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). This that retinol be the the retinaldehyde be The LD50 for Adh1 -/- mice was reduced 3-fold with the LD50 for Raldh1 -/- mice was reduced plays a more role than RALDH1 in retinol a dose of excessive accumulation of serum retinol in Adh1 -/- accumulation of retinol in Raldh1 -/- mice was only than We excessive accumulation of retinaldehyde in Raldh1 -/- mice following retinol and be for increased toxicity in mice in the LD50 serum retinaldehyde levels were in Adh1 -/- mice toxicity was evidence that excessive accumulation of retinol rather than retinaldehyde is the to toxicity after retinol indicate that mechanisms for retinaldehyde exist a large in the of retinaldehyde have in a large accumulation of retinol to the of the by We that RA was produced a in the of that enzyme can oxidize retinaldehyde to RA in adult mice. This of RA have sufficient to Raldh1 -/- mice to retinol toxicity, but it is that retinaldehyde was also metabolized in that the step in of retinol toxicity in the oxidative metabolism of retinol to retinaldehyde by toxicity than of retinol pathways include are known to retinol to (23Roberts E.S. Vaz A.D.N. Coon M.J. Mol. Pharmacol. 1992; 41: 427-433PubMed Google Scholar). metabolism of to toxicity as metabolism and that can J. Clin. 1994; PubMed Scopus Google Scholar, Yin M. J.M. F.J. T. A. M.B. Am. J. 277: PubMed Google Scholar). of retinol by ADH retinaldehyde by not produce it with the pathway of retinol is to W.S. J.A. Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. 2nd Ed. Raven Press, Ltd., New York1994: Scholar). excessive of in toxicity as to greatly the of acid to of to Pharmacol. PubMed Scopus Google Scholar). are several Adh1 and Raldh1 that evidence that are in the metabolic to Raldh1 -/- Adh1 -/- mice also do not have defects in or (26Molotkov A. Deltour L. Foglio M.H. Cuenca A.E. Duester G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). This to a function for both and RALDH1 in of adult toxic or is the ADH in mouse Eur. J. Biochem. PubMed Scopus Google Scholar, M. Foglio M.H. Duester G. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Duester G. Alcohol. Clin. Exp. Res. 1997; PubMed Scopus Google Scholar), and RALDH1 is also in mouse I. Duester G. Dev. PubMed Google Scholar), that a function for both enzymes is the of toxic in the and RALDH1 are both easily in a of adult tissues and that function in metabolic pathways in several adult and RALDH1 can as and (10Boleda M.D. Saubi N. Farrés J. Parés X. Arch. Biochem. Biophys. 1993; 307: 85-90Crossref PubMed Scopus (180) Google Scholar, Eur. J. 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